Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML

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PROJECT SUMMARY/ABSTRACT Dr. Haijiao Zhang has been training as a medical student for 7 years with a focus on hematological malignancies and as a researcher for 6 years in the field of characterizing oncogene and drug resistance mechanisms. Her research has led to 8 published manuscripts and 4 other manuscripts in submission /preparation. The theme of Dr. Zhang's research involves systematic characterization of leukemia oncogenes and understanding leukemia drug resistance mechanisms. She has characterized 4 distinct mechanisms of CSF3R mutations and diverse mechanisms associated with drug resistance to the FLT3 inhibitor crenolanib. The WT1 (Wilms' tumor 1) gene encodes a transcription factor with C-terminal zinc-finger domains, whereas the N-terminal part contains domains that mediate receptor dimerization, RNA recognition, and transcriptional regulation. WT1 mutations are present in approximately 10–15% of AML and are associated with chemotherapy resistance and disease relapse. WT1 mutations are frameshift mutations or substitutions across all structural domains, predominantly in exons 7 and 9. The pathogenesis mediated by loss-of-function of WT1 zinc finger domain mutations has been studied; however very little is known about the oncogenic potential, drug sensitivity, and the structural basis of mutations residing in other domains of WT1. In the current proposal, Dr. Zhang will evaluate the functional consequences of these mutations and characterize the mechanisms associated with the growth/survival advantage and a higher propensity for chemotherapy resistance of WT1 mutations. She also aims to identify therapeutics with enhanced efficacy in the WT1 mutant setting. Using ex vivo inhibitor screening on primary leukemia patient samples, she has determined that inhibitors of BCL2 and RAF/ERK pathways demonstrated higher efficacy against WT1 mutant samples compared with controls. She will validate these findings using NRG mouse model. Finally, she will investigate the phenotypic, mechanistic, and therapeutics targeting WT1 combinatorial mutation. Dr. Zhang's long-term career goals include the establishment of an independent research lab focusing on systematic characterization of oncogenic mutations and chemotherapy resistance to better predict the clinical relevance of mutations and identify novel therapeutics to circumvent chemotherapy resistance. During the mentored phase, she will continue to receive excellent mentorship from Dr. Jeffrey Tyner, an expert on functional genomics and targeted therapy. She will receive co-mentorship from Dr. Ravi Majeti, an expert in leukemia stem cell biology, CRISPR editing, and high-fidelity xenotransplantation mouse models, which she will use in the current project. The proposed research will also be enhanced by guidance from Dr. Brian Druker, a pioneer in translational medicine and targeted therapies for cancer; and Dr. Shannon McWeeney who will provide guidance in bioinformatics analyses. Additionally, Dr. Tyner, Dr. Majeti, and the advisory team will assist her in navigating the transition to an independent faculty position.